Title: Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein
Authors: Strating, Jeroen R P M
van der Linden, Lonneke
Albulescu, Lucian
Bigay, Joëlle
Arita, Minetaro
Delang, Leen
Leyssen, Pieter
van der Schaar, Hilde M
Lanke, Kjerstin H W
Thibaut, Hendrik Jan
Ulferts, Rachel
Drin, Guillaume
Schlinck, Nina
Wubbolts, Richard W
Sever, Navdar
Head, Sarah A
Liu, Jun O
Beachy, Philip A
De Matteis, Maria A
Shair, Matthew D
Olkkonen, Vesa M
Neyts, Johan
van Kuppeveld, Frank J M # ×
Issue Date: Feb-2015
Publisher: Elsevier Inc
Series Title: Cell Reports vol:10 issue:4 pages:600-615
Article number: S2211-1247(14)01121-8
Abstract: Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication, whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e., shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs.
ISSN: 2211-1247
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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